Estrogenic substances are commonly used in methods of Hormone Replacement Therapy (HRT) and methods of female contraception. These estrogenic substances can be divided in natural estrogens and synthetic estrogens. Examples of natural estrogens that have found pharmaceutical application include estradiol, estrone, estriol and conjugated equine estrogens. Examples of synthetic estrogens, which offer the advantage of high oral bioavailability include ethinyl estradiol and mestranol.
Estetrol [estra-1,3,5(10)-trien-3,15α,16α,17β-tetraol; CAS Nr. 15183-37-6] is a biogenic estrogen that is endogeneously produced by the fetal liver during human pregnancy. In this description the IUPAC-recommended ring lettering and atom numbering for steroids and steroid derivatives, as depicted below, are applied.

Estetrol has been found effective as an estrogenic substance for use in HRT (EP 1 390 040 B1, EP 1 446 128 B1), contraception (EP 1 390 041 B1, EP 1 390 042 B1), therapy of auto-immune diseases (EP 1 511 496 B1), prevention and therapy of breast and colon tumors (EP 1 526 856 B1), enhancement of libido (EP 1 390 039 B1), treatment of infertility (EP 2 114 412 B1), treatment of acute vascular disorder (EP 1 971 344 B1), skin care and wound healing (EP 1 511 498 A1).
The synthesis of Estetrol on a laboratory scale is for example disclosed in Fishman et al., J. Org. Chem. 1968, 33, 3133-3135, wherein Estetrol is synthesized from estrone derivative III as shown in Scheme 1 (numbering according to Fishman et al).

According to Fishman et al., oxidation of the allylic diacetate VIb with OsO4 produced as the desired product Ib together with a small amount of the isomeric 15β,16β-diol. The authors did not quantify the isomeric mixture. The yield of the dihydroxylation is 47% and the overall yield of the 3-step process shown in Scheme 1 is, starting from estrone derivative III, about 7%.
Another synthesis of Estetrol wherein estrone is the starting material is disclosed in Nambara et al., Steroids 1976, 27, 111-121. This synthesis is shown in Scheme 2 (numbering according to Nambara et al.). The carbonyl group of estrone I is first protected by treatment with ethylene glycol and pyridine hydrochloride followed by acetylation of the hydroxyl group at C3. The next sequence of steps involved a bromination/base catalyzed dehydrobromination resulting into the formation of 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol (compound IVa). This compound IVa was subsequently acetylated which produced 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol-3-acetate (compound IVb). In a next step, the dioxolane group of compound IVb was hydrolysed by using p-toluene sulfonic acid to compound Vb, followed subsequently by reduction of the carbonyl group at C17 (compound Vc), acetylation (compound Vd) and oxidation of the double bond of ring D thereby forming estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3,17-diacetate (compound VIb). Neither experimental protocol nor details about the yield or selectivity of said oxidation of the double bond of ring D are provided in Nambara et al.

Suzuki et al., Steroids 1995, 60, 277-284 also discloses the synthesis of Estetrol by using compound Vb of Nambara et al. as starting material. The carbonyl group at C17 of this compound was first reduced followed by acetylation yielding estra-1,3,5(10),15-tetraene-3,17-diol-3,17-diacetate (compound 2b). The latter was subjected to oxidation with OsO4 which provided estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3, 17-diacetate (compound 3b) in 46% yield, along with the isomeric 15β,16β-diol as impurity (15α,16α/15β,16β isomeric ratio=74/26).

According to Nambara et al. and Suzuki et al., the synthesis of Estetrol can be performed with a yield of approximately 8%, starting from estrone.
A process for the preparation of Estetrol that is suitable for the preparation of this compound on an industrial scale is disclosed in WO 2004/041839 A2. This process is shown in Scheme 4 (numbering according to WO 2004/041839), and comprises the following steps:                1) converting estrone (7) into 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (6), wherein A is a protecting group, this step involving in turn five sub-steps;        2) reduction of the 17-keto group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (6) to 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol (5);        3) protection of the 17-OH group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol (5) to 3-A-oxy-17-C-oxy-estra-1,3,5(10),15-tetraene (4), wherein C is a protecting group;        4) oxidizing the carbon-carbon double bond of ring D of 3-A-oxy-17-C-oxy-estra-1,3,5(10),15-tetraene (4) to protected Estetrol (3); and        5) removing the protecting groups, wherein preferably protecting group A is removed first to form 17-OC protected Estetrol (2) and subsequently protecting group C is removed to form Estetrol (1);                    wherein the protecting group A is selected from an C1-C5 alkyl group or a C7 C12 benzylic group and the protecting group C is selected from monofunctional aliphatic hydroxyl protecting groups.                        

With the method as disclosed in WO 2004/041839 and shown in Scheme 4 above, Estetrol is obtained in an overall yield of 10.8%, starting from estrone. Specifically, the yield of the cis-dihydroxylation step as described in the example 9 is 43% after three crystallizations in order to purify the product from the 15β,16β-diol isomer. Although the process disclosed in WO 2004/041839 is suitable for an industrial scale preparation of Estetrol, the high number of synthetic steps and the isolation and purification of each intermediate product results in a loss of yield, thereby reducing the overall yield of Estetrol. Furthermore, the conversion of 7 into 6 involves a halogenation and a dehalogenation step, typically a bromination and a debromination step. In particular during said halogenation and dehalogenation reactions, various side products are produced.
Another process for the preparation of Estetrol on an industrial scale is disclosed in WO 2013/012328 A1. This process, depicted in Scheme 5 below, comprises the following steps:                (1) conversion of estrone (II) into 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene (III), wherein A is a protecting group and B is —Si(R2)3;        (2) conversion of 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene (III) into 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (IV), wherein A is a protecting group;        (3) reduction of the 17-keto group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (IV) to form 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol (V), wherein A is a protecting group;        (4) protection of the 17-OH group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol V to form 3-A-oxy-17-C-oxy-estra-1,3,5(10),15-tetraene (VI), wherein A and C are protecting groups;        (5) oxidation of the carbon-carbon double bond of ring D of 3-A-oxy-17-C-oxy-estra-1,3,5(10),15-tetraene (VI) to form protected Estetrol (VII), wherein A and C are protecting groups; and        (6) removal of protecting groups A and C to form Estetrol (I);                    wherein:                            A is a protecting group selected from the group consisting of a C1-C5 alkyl group, a C7-C12 benzylic group and a-Si(R1)3 group, wherein R1 is independently selected from the group consisting of a C1-C6 alkyl group and a C6-C12 aryl group;                B is —Si(R2)3, wherein R2 is independently selected from the group consisting of a C1-C6 alkyl group and a C6-C12 aryl group; and                C is a protecting group selected from the group consisting of monofunctional aliphatic hydroxyl protecting groups.                                                

The yield reported for step 5, oxidation of the carbon-carbon double bond from the intermediate product (VI) to form protected Estetrol (VII), is 43% after purifications, with a purity of 98.7%. If a Palladium catalyst is used, the cost of the process increases to a large extent.
WO 2013/034780 A2 discloses a process for obtaining Estetrol and derivatives thereof of formula (I)

or a salt or solvate thereof, wherein R represents H or an hydroxyl protecting group; the process comprising reacting a compound of formula (II) wherein R is as defined previously, with an oxidizing agent. The process avoids the need of using protecting groups at the β-hydroxyl group at C17, thus simplifying it, and it has been found to provide high stereoselectivities in favor of the desired α,α-isomer as well, on average ≥90%.
WO 2013/050553 A1 discloses a multi-step process for the preparation of Estetrol as depicted in Scheme 7:

wherein P1 is a protecting group selected from R1CO—, or R2Si(R3)(R4)—, P2 is a protecting group selected from (R6R5R7)C—CO—, or (R2)Si(R3)(R4)—, wherein R1 is a group selected from C1-6 alkyl or C3-6 cycloalkyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4 alkyl; R2, R3 and R4 are each independently a group selected from C1-6 alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4 alkyl; R5 is a group selected from C1-6 alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4 alkyl; R6 and R7 are each independently hydrogen or a group selected from C1-6 alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4 alkyl.
The disclosed process is alleged to allow the preparation of estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol as the major product with little or no estra-1,3,5(10)-triene-3,15β,16β,17β-tetrol isomer by an oxidation agent selected from KMnO4, OsO4, H2O2 or I2/Ag(OAc)2, but in fact, there are neither data nor examples to support this observation.
When the inventors repeated the procedures disclosed in said application regarding the dihydroxylation reaction to obtain the 15-alpha, 16-alpha diol using KMnO4 as oxidant (Examples 1 and 2 in WO2013/050553), such product was not observed. In all the cases the starting material was recovered together with 1-2% of the 15-betha, 16-betha diol, instead of the 15-alpha, 16-alpha diol claimed in said patent application (see comparative Examples 1 and 2 in the present application),
In most cases the processes disclosed in the state of the art comprise a high number of synthetic steps, affecting the overall yield in which Estetrol is obtained. Further, the oxidation of the carbon-carbon double bond of ring D typically proceeds with a poor or moderate stereoselectivity, obtaining relatively large amounts of the undesired isomeric 15β,16β-diol.
In view of the above, it is still necessary to provide an alternative process for obtaining Estetrol on an industrial scale, which allows the production of this compound in a high yield, and at the same time, minimizes the impurities associated.